Targeting GSDMD JX06 inhibits PANoptosis and multiple organ injury
Shiyi Chen1, Guo-Dong Wu1, Tongfu Li1
1Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240 PR China; National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai 200240 PR China.
Abstract:
Multiple organ dysfunction syndrome (MODS) is the major cause of mortality of patients in intensive care units. The elusive mechanisms of tissue damage in MODS and limited therapeutic options encourage us to seek effective therapies to MODS. PANoptosis has recently been proven to be the key player in both heat stress and sepsis-mediated MODS. Therefore, we initially investigated the role of gasdermin D (GSDMD) in heat stress and sepsis-induced MODS. We found that GSDMD deficiency attenuates heat stress or sepsis mediated cell death, tissue inflammation and severe multiple organ injury (MOI). Next, we screened out and proved that JX06 effectively inhibited GSDMD-NT mediated cell death, by covalently modifying the Cys39/192 residue in GSDMD, inhibiting the accumulation of GSDMD-NT and pore formation in cell membrane. In vivo, JX06 administration attenuated heat stress and sepsis-mediated cell death, inflammation, MODS and animal mortality via suppressing GSDMD-mediated PANoptosis. Overall, our results indicated that GSDMD is critical for MODS by executing PANoptosis; administrating its inhibitor, JX06, effectively suppresses MODS by inhibiting PANoptosis, and suggesting that JX06 would be an effective drug candidate for MODS and related death.
Insights
Gasdermin D (GSDMD) drives multiple organ dysfunction syndrome (MODS) through PANoptosis. Inhibiting GSDMD with JX06 effectively suppresses MODS, offering a potential therapeutic strategy for critical care patients.
Area of Science:
- Immunology
- Cell Biology
- Critical Care Medicine
Background:
- Multiple organ dysfunction syndrome (MODS) is a leading cause of mortality in intensive care units.
- The precise mechanisms underlying tissue damage in MODS remain elusive, necessitating novel therapeutic approaches.
- PANoptosis has emerged as a critical cellular process implicated in heat stress and sepsis-induced MODS.
Purpose of the Study:
- To investigate the role of gasdermin D (GSDMD) in heat stress and sepsis-mediated MODS.
- To identify and validate inhibitors of GSDMD activity for potential therapeutic intervention.
- To elucidate the mechanism by which JX06 exerts its protective effects in MODS.
Main Methods:
- GSDMD deficiency models were used to assess its role in cell death and organ injury.
- A novel inhibitor, JX06, was screened and characterized for its ability to inhibit GSDMD.
- In vivo studies evaluated the efficacy of JX06 in attenuating MODS and mortality in heat stress and sepsis models.
Main Results:
- GSDMD deficiency significantly reduced cell death, inflammation, and multiple organ injury in response to heat stress and sepsis.
- JX06 was identified as a covalent inhibitor of GSDMD, preventing GSDMD-N-terminal (GSDMD-NT) accumulation and pore formation.
- Administration of JX06 attenuated MODS, inflammation, and mortality in vivo by suppressing GSDMD-mediated PANoptosis.
Conclusions:
- GSDMD plays a critical role in executing PANoptosis, thereby contributing to MODS.
- JX06 effectively inhibits GSDMD-mediated PANoptosis, demonstrating significant therapeutic potential for MODS.
- JX06 represents a promising drug candidate for the treatment of MODS and associated mortality.
